Immune tolerance is central to the immune system's ability to differentiate between self and foreign proteins. Central tolerance is initially achieved during thymic selection by the deletion of self-reactive T cells. However, central tolerance is incomplete, and further immune regulation is required in the periphery. Peripheral mechanisms of T cell regulation include the induction of anergy, activation induced cell death, and regulatory T cells.
Within the CD4+ T lymphocyte cell population, several categories of regulatory T cells have been described. In general, these subpopulations are classified according their site of development and/or the cytokines they produce. One subset of regulatory T cells develops in the thymus (natural regulatory T cells) while a different subset differentiates from CD4+CD25− precursors after leaving the thymus and encountering specific antigen in the periphery (inducible regulatory T cells). Among inducible regulatory T cell subsets, Trl cells secrete IL-10, while Th3 cells secrete TGF-β, although both cell types have been shown to produce both IL-10 and TGF-β to some extent. More recently, investigators have shown that the expression of forkhead box protein P3 (“Foxp3”) transcription factor is an important marker in the classification of regulatory T cells.
Given the important role CD4−CD25+ regulatory T cells play in immune tolerance, there is a need to develop methods for generating, selecting, and expanding human antigen-specific regulatory CD4+CD25+ T cells from the peripheral blood of a subject in need thereof for use in the treatment and/or prevention of autoimmune disorders, allergies, inflammatory conditions and for the prevention of graft rejection in a recipient following solid organ, tissue, bone marrow, or stem cell transplantation.